Pd-Catalyzed Csp2-H Functionalization of Heteroarenes via Isocyanide Insertion: Concise Synthesis of Di-(Hetero)Aryl Ketones and Di-(Hetero)Aryl Alkylamines

Article abstract of DOI:10.1002/chem.201406562

We report herein an efficient Pd-catalyzed direct C-H bond functionalization of heteroarenes via an isocyanide insertion strategy for the synthesis of di-(hetero)aryl ketones and di-(hetero)aryl alkylamines. The methodology involves a three component reaction between an azole, a haloarene and an isocyanide resulting in the formation of an imine, which in turn is either hydrolyzed or reduced to get the desired product.

Full text of DOI:10.1002/chem.201406562

DOI: 10.1002/chem.201406562
Communication
&
C-H Functionalization
Pd-Catalyzed Csp2ÀH Functionalization of Heteroarenes via
Isocyanide Insertion: Concise Synthesis of Di-(Hetero)Aryl Ketones
and Di-(Hetero)Aryl Alkylamines
Upendra K. Sharma,[a] Nandini Sharma,[a] Jun Xu,[a, b] Gonghua Song,[b] and
Erik V. Van der Eycken*[a]
pling with a-oxo-carboxylic acids. Nonetheless the method re-
quires relatively harsh reaction conditions and long reaction
times (Scheme 1, ii).[7e] Thus, it would be highly desirable if
such acylations could be achieved by employing readily avail-
able precursors in a milder way.
Abstract: We report herein an efficient Pd-catalyzed direct
CÀH bond functionalization of heteroarenes via an isocya-
nide insertion strategy for the synthesis of di-(hetero)aryl
ketones and di-(hetero)aryl alkylamines. The methodology
involves a three component reaction between an azole,
a haloarene and an isocyanide resulting in the formation
of an imine, which in turn is either hydrolyzed or reduced
to get the desired product.
Isocyanides, which are an economic and safe alternative for
CO, are irreplaceable building blocks in organic synthesis[8] and
have found profound applications as versatile C1 synthons in
transition-metal catalysis.[9] Since the pioneering work of Pass-
erini[10a] and Ugi[10b] the past decade has witnessed a rapid in-
Direct CÀH bond functionalization of (hetero)arenes
promoted by transition metals is a valuable tool for
the facile synthesis of diversified organic molecules,
as it circumvents the need for pre-functionalization.[1]
The heteroaryl azole skeleton[2] is a key structural unit
in various biologically active compounds and finds
profound applications in medicinal chemistry as well
as in material sciences.[3] Over the years, substantial
progress has been made in the direct arylation, alke-
nylation and alkynylation of azoles using aryl halides
and pseudohalides as coupling partners.[4] Recently,
some efficient methods have emerged regarding the
direct alkylation[5,6] and acylation[7] of such heteroar-
enes. In contrast, the installation of a secondary alkyl-
Scheme 1. Methods towards acylation and secondary CÀH alkylation of azoles.
amine group on an azole has been confined to a few
reports only (Scheme 1, iii).[6e] Among the various
strategies for the acylation of azoles, transition-metal-catalyzed
carbonylation has received much attention (Scheme 1, i).[7c]
However, long reaction times, high pressure, and toxicity of CO
limit the application of such reactions. Very recently, Ge and
co-workers have reported an attractive methodology for the
acylation of heteroarenes employing a decarboxylative cou-
crease in various CÀC-bond-forming reactions involving isocya-
nides.[8–10] However, their use in CÀH activation processes is
much less explored especially under intermolecular conditions.
Herein, we report an efficient methodology for the synthesis of
a di(hetero)aryl framework through the insertion of an isocya-
nide into an aryl halide bond, followed by attack of a heterocy-
cle in a domino fashion via CÀH activation (Scheme 2).
Systematic studies revealed that di(hetero)aryl imine 3aa
can be synthesized (98% GC-MS yield, 90% isolated) from bro-
mobenzene 1a (0.2 mmol), tert-butyl isocyanide 2a
(0.24 mmol) and 2-phenyl-1,3,4-oxadiazole 3a (0.24 mmol) in
the presence of Pd(OAc)2 (5.0 mol%), Xantphos (5.0 mol%) and
Cs2CO3 (0.4 mmol) at 1108C for 6 h with MeCN as solvent (for
details, see Supporting Information Table S1). Subsequently,
mild silica gel promoted hydrolysis of 3aa in dichloromethane
at room temperature afforded di(hetero)aryl ketone 4aa in
high yield.
[a] Dr. U. K. Sharma, Dr. N. Sharma, J. Xu, Prof. Dr. E. V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC)
Department of Chemistry, University of Leuven (KU Leuven)
Celestijnenlaan 200F, 3001 Leuven (Belgium)
E-mail: erik.vandereycken@chem.kuleuven.be
Homepage: http://chem.kuleuven.be/en/research/mds/lomac
[b] J. Xu, Prof. Dr. G. Song
Shanghai Key Laboratory of Chemical Biology, East China University of Sci-
ence and Technology, Shanghai 200237 (PR China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406562.
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conversion of imine 3aa using two equivalents of
zinc dust in alkaline solution[11c] at 608C for 2 h under
ultrasonication, providing 6aa in 62% yield. The re-
sults summarized in Table 4 show that imines derived
from tert-butyl-, cyclohexyl- and 1,1,3,3-tetramethyl-
butyl isocyanide gave the corresponding secondary
amines in moderate to good yields (6aa–6al). How-
ever, only trace amounts of desired compound were
observed in case of imines resulting from linear iso-
cyanides such as n-butyl or n-pentyl. Also, the reac-
tion was found highly susceptible to the nature of
substitution. Whereas low to moderate yields were
obtained with substituted oxadiazoles (6ad–6ag), the pres-
ence of an electron-donating or electron-withdrawing group
on the aryl bromide gave the corresponding products in good
Scheme 2. A typical isocyanide insertion versus CÀH activation.
Having established the optimal reaction conditions, we sub-
sequently investigated the influence of different isocyanides
on the efficiency of the insertion reaction (Table 1). While tert-
butyl-, n-butyl- and 1,1,3,3-tetramethylbutyl isocyanide provid-
ed almost similar yields (entries 1–3), a significantly lower yield
was obtained with cyclohexyl isocyanide (entry 4). Only traces
(<10%) were observed with benzyl isocyanide (entry 5) while
the reaction failed completely with p-methoxyphenyl isocya-
nide (entry 6).
Table 1. Effect of different isocyanides on the insertion reaction.[a]
Then, we evaluated the scope of this methodology for differ-
ent aryl halides with 2-phenyl-1,3,4-oxadiazole and tert-butyl
isocyanide (Table 2). The reaction proceeded well with various
substituted aryl bromides, phenyl iodide and phenyl triflate
(4aa–4ak). However, it failed completely with phenyl chloride.
The satisfying formation of o-subsituted heteroaryl ketone 4af
in contrast to the work of Ge and co-workers[7e] is particularly
notable. Heteroaryl bromides (4ah–4ag) and bulky 1-naphthyl
or 4-biphenyl bromide (4aj–4ak) were also found to be good
coupling partners to give products in good to high yields.
Subsequently, the scope of different oxadizole derivatives
and related azoles with similar structures was investigated
(Table 3). Good to high yields were obtained in the presence of
electron-donating or electron-withdrawing groups (5aa–5ae)
on the phenyl ring of the oxadiazole, except in case
of nitro derivative (5af). Also, replacement of the
phenyl ring of the oxadiazole with a benzyl group
(5ag) or a 3-pyridyl ring (5ah) led to the desired
products in high yields.
Entry
R1
Yield [%][a,b]
1
tBu
nBu
TMB
Cy-hexyl
benzyl
PMP
88 (98)
85 (88)
91 (99)
69 (75)
traces
n.d
2[c]
3
4[d]
5[e]
6[e]
[a] Isolated yield of hydrolysed product under optimized conditions. [b]
Yield of imine determined by GC-MS (in parenthesis). [c] Yield of imine
after 4 h. [d] Yield of imine after 3 h. [e] After 24 h. TMB = 1,1,3,3-tetra-
methylbutyl; PMP = p-methoxyphenyl.
Similarly, good yields were obtained with 2-phenyl
oxazole (5ai) and benzoxazole (5ak) while relatively
lower yields were observed with sulfur analogues 5aj
and 5al. However, the reaction was not found com-
patible with nitrogen analogues such as N-methyl
indole, benzimidazole and caffeine.
Further, to utilize the third diversity point resulting
from the isocyanide and to enhance the practical util-
ity of our methodology, we targeted the synthesis of
azoles bearing an alkylamine side chain at their C2
position, as this entity is present in many natural
products and drugs.[11a] Therefore we envisioned the
reduction of the generated N-alkyl imine intermedi-
ate 3aa. Compared with the reduction of C=O and
C=C bonds, the reduction of C=N bonds remains
a big challenge due to its weak reactivity.[11b] After
several attempts, we were able to achieve complete Scheme 3. Control experiments and deuterium-labelling studies.
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to high yields (6ah–6aj). Importantly, the use of het-
eroaryl halides such as thiophene (6ak) or bulky
naphthalene (6al) was found to be feasible, thereby
enabling a facile diversification into biologically im-
portant biheterocyclic frameworks.
Table 2. Scope of different aryl halides with 2-phenyl-1,3,4-oxadiazole.[a,b]
To get more insight in the reaction mechanism
some control experiments were carried out
(Scheme 3). In the absence of isocyanide 2a as reac-
tion partner, direct arylated oxadiazole 7a was ob-
served, which was also a side product encountered
in few cases. Likewise when oxadiazole 3a was omit-
ted from the reaction, formation of amide 8a was
observed in low yield. Moreover, the presence of
TEMPO did not hamper the reaction, ruling out the
possibility of a free radical mechanism. Further, rapid
H/D scrambling was noticed upon exposure of 2-deu-
tero-oxadiazole [D1]-3a to the catalytic conditions
after one hour. The kH/kD was equal to 1.06 which in-
dicates that the CÀH activation step is reversible and
might not be the rate determining step for this pro-
cedure.[12] Based on these outcomes, we propose the
following reaction mechanism (Scheme 4). Initially,
the oxidative addition of arylbenzene onto a ligated
Pd0 species generates the aryl–PdII complex A. This is
followed by isocyanide insertion to form B which
could be trapped by 3a via base-assisted bromide
exchange to form C. Reductive elimination of the
imine from C completes the catalytic cycle and re-
generates the active palladium species. The resulted
imine could be hydrolyzed with silica gel or reduced
to give the desired products. The aryl–PdII complex A
can also be trapped by 3a leading to the formation
of 7a which is an expected side reaction for this
domino transformation.[7c] Moreover, the formation of
8a as side product can be ascribed to trapping of B
by residual H2O.[9j,k]
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), tert-butyl isocyanide
(0.24 mmol), Pd(OAc)2 (5 mol%), Xantphos (5 mol%), Cs2CO3 (0.4 mmol) in MeCN
(2.0 mL) at 1108C for 6 h. [b] Isolated yields. [c] DMSO as solvent; X = Br unless men-
tioned.
Table 3. Scope of different azoles with aryl bromide.[a,b]
The practical applicability of the process for the
synthesis of heteroaryl–ketones was successfully
demonstrated by up-scaling the reaction to the gram
scale, affording 4aa in 80% yield (Scheme 5).
In conclusion, an efficient methodology involving
Pd-catalyzed Csp2ÀH functionalization of heteroarenes
via isocyanide insertion has been elaborated for the
synthesis of di-(hetero)aryl imines which could then
be hydrolyzed or reduced to access synthetically and
biologically relevant di-(hetero)arylketones or di-(het-
ero)aryl amines, respectively. The broad substrate
scope, the readily available starting materials, the rel-
atively mild reaction conditions and the good yields
make this method synthetically useful.
Experimental Section
To an oven dried 10 mL screw cap vial equipped with
a stir-bar were added aryl halide 1a (0.2 mmol), Pd(OAc)2
(5 mol%), Xantphos (5 mol%), base (0.4 mmol), isocya-
nide 2a (1.2 equiv), acetonitrile (2 mL) and heteroarene
[a] Optimized conditions as in Table 2. [b] Isolated yields. [c] Optimum yield of imine
after 4 h. [d] With LiOtBu. [e] Optimum yield of imine after 24 h.
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3a (1.2 equiv). The mixture was degassed, backfilled
with nitrogen and then stirred under nitrogen at 1108C
for 6 h. The resulting reaction mixture was cooled to
ambient temperature, diluted with ethyl acetate (5 mL)
and passed through a small bed of celite and concen-
trated under vacuum to provide crude imine. The crude
imine was then hydrolyzed with silica gel in DCM at RT
overnight or reduced under the optimized conditions.
The resulting mixture was filtered, concentrated, and
then the crude product was purified by column chro-
matography on silica gel using heptane/EtOAc as
Table 4. Scope for secondary amines.[a,b]
1
eluent. The products were further identified by H, 13C
NMR and HR-MS, which were all in good agreement
with the assigned structures.
Acknowledgements
Support was provided by the Research Fund of the
University of Leuven (KU Leuven) and the FWO
(Fund for Scientific Research Flanders (Belgium).
U.K.S. and N.S. are thankful to KU Leuven for provid-
ing post-doctoral fellowship. J.X. is thankful to the
CSC, China for providing a doctoral exchange schol-
arship.
Keywords: azoles · CÀH activation · heteroarenes ·
isocyanide insertion · palladium
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Received: December 19, 2014
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COMMUNICATION
&
C-H Functionalization
U. K. Sharma, N. Sharma, J. Xu, G. Song,
E. V. Van der Eycken*
&& – &&
Pd-Catalyzed Csp2ÀH
Functionalization of Heteroarenes via
Isocyanide Insertion: Concise
Synthesis of Di-(Hetero)Aryl Ketones
and Di-(Hetero)Aryl Alkylamines
Functionalized azoles: Pd-catalyzed
direct CÀH bond functionalization of
heteroarenes via an isocyanide insertion
strategy (see scheme) for the synthesis
of di-(hetero)aryl ketones and di-
(hetero)aryl alkylamines is described.
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